7. PROJECT SUMMARY/ABSTRACT Sungjune Kim, MD, PhD, PI ? PA-14-046 (K08 Resubmission) 11/12/15 Title: Epigenetic modulation of immune tolerance by ionizing radiation and chemotherapy Cancer immunotherapy represents a paradigm shift in the management of cancer. Recent successes with antibody directed therapies for immune modulators CTLA4 and PD1/PDL-1 have altered the landscape of systemic therapy for melanoma and other solid cancers. While felt to be the most immunogenic among cancers, melanoma exhibits a wide spectrum of immune tolerance mechanisms, and a majority of patients fail to elicit clinically significant antitumor immune responses. The response rates for other solid cancers are even lower. Therefore, developing modalities to enhance immunotherapy, such as radiation therapy (XRT) or conventional chemotherapy, represent an active area of investigation. Because most cancer patients receive XRT or chemotherapy at some point in their disease process, harnessing the immunogenic potential of these modalities is of pivotal importance. Our preliminary clinical and preclinical data suggest cytotoxic therapy induce a net positive impact on immune activation, but limited by tolerogenic mechanisms also evoked. Interestingly, cytotoxic therapy induces a profound up-regulation of HDAC6, a positive regulator of tolerogenic cytokine IL-10 mediating immune tolerance. HDAC6 inhibition resulted in radiosensitization and enhanced immunogenicity by cytotoxic therapy. Based on these observations, we propose to overcome the tolerogenic effects of HDAC6 induction by cytotoxic therapy. The central hypotheses to be tested in this grant are whether manipulation of HDAC6 augments therapeutic efficacy and immunogenicity of cytotoxic therapy in melanoma. This research will translate into clinical trials testing HDAC6-specific inhibitors as a novel class of therapeutic agents to sensitize melanoma for cytotoxic therapy alone, or in combination with immunotherapy. The proof in concept defined in melanoma will be applicable to other cancers.